title: NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis.
abstract: BACKGROUND
  The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity.
  
  
  METHODS
  A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS.
  
  
  CONCLUSIONS
  This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene.
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Bókay J. u. 53, Budapest 1083, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kerti
authors.forename: Rózsa
authors.initials: R
authors.lastname: Csohány
authors.forename: László
authors.initials: L
authors.lastname: Wagner
authors.forename: Eszter
authors.initials: E
authors.lastname: Jávorszky
authors.forename: Erika
authors.initials: E
authors.lastname: Maka
authors.forename: Kálmán
authors.initials: K
authors.lastname: Tory
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D018450:Disease Progression; D060045:Genes, Modifier; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D040941:Heredity; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000235:genetics; D007797:Laminin / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D051762:PAX2 Transcription Factor / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics; D012307:Risk Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D008565:Membrane Proteins; C407223:NPHS2 protein; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; C058783:laminin beta2